1. Field of the Invention
The present invention relates to tumor diagnosis and therapy. In particular, it is directed to the diagnosis and therapy of tumors carrying GnRH receptors.
2. State of the Art
Post-operative treatment of prostate and mammary carcinomas with agonists of gonadotropin releasing hormone (GnRH, in the literature also referred to as luteinizing hormone releasing hormone; LH-RH) is a standard treatment; cf. Gonzalez-Barcena et al., 1994, The Prostate 24, 84-92; Emons and Schally, 1994, Human Reproduction Update 9, No. 7, 1364-1379. The GnRH receptor is a well-known target in tumor therapy.
Thus, in various steroid hormone (sexual hormone) dependent malignant tumors, such as mammary carcinoma, prostate carcinoma, ovarian carcinoma, and endometrial carcinoma, a double effect has been observed in clinical studies upon treatment with GnRH agonists:
1) an indirect anti-proliferative activity by uncoupling of the positive endocrine (estrogenous or androgenous) effect on tumor growth;
2) a direct anti-proliferative activity by an unknown mechanism via GnRH receptors in the tumor tissue itself; cf. Emons and Schally, 1994, Human Reproduction Update 9, 1364-1379.
This indirect effect due to steroid hormone dependence has been known for decades for the prostate and the mammary carcinoma; cf. Gonzalez-Barcena et al., 1994, The Prostate 24, 84-92; Jonat et al., 1995, European Journal of Cancer 31A, 137-142.
The direct anti-proliferative effect of GnRH agonists and GnRH antagonists on e.g. prostate carcinomas, mammary carcinomas, and ovarian carcinomas has been confirmed by clinical studies. Some of the GnRH agonists employed in these treatments having a direct anti-proliferative effect are known by the following trademarks of the medicaments approved in Germany: for example ZOLADEX®, ZOLADEX 10.8®, ZOLADEX GYN®, PROFACT®-DEPOT, PROFACT® PRO INJECTIONE/NASAL, SYNARELA®, ENANTONE MONATS-DEPOT®, UNO-ENANTONE®, ENANTONE GYN MONATS-DEPOT®, TRENANTONE®, SUPRECUR®, CARCINIL®, or DECAPEPTYL® 0.5 mg/0.1 mg, DECAPEPTYL® DEPOT, DECAPEPTYL® GYN as well as DECAPEPTYL® DIAGNOSTIK.
Research with cell culture has revealed that GnRH receptors are present on human primary liver cell carcinomas and pancreas adenocarcinomas. In addition, the beginning of a biochemical metabolization with respect to cleavage of GnRH between tyrosine 5 and glycine 6 in rat glioma and rat neuroblastoma has been described; cf. Tao et al., 1991, Neuropeptides 20, 125-131. Ligand binding of GnRH to the GnRH receptor and its signal transduction, however, takes place in a different way, namely at the eighth amino acid of GnRH, arginine, and this exclusively occurs in the case of an intact conformation of the GnRH molecule and its amino acid side chains (Naor, Z., Schacham, Sh., Harris, D., Seger, R., and Reiss, N., 1995, Signal Transduction of the Gonadotropin Releasing Hormone (GnRH) Receptor: Cross-Talk of Calcium, Protein Kinase C (PKC), and Arachidonic Acid. Cellular and Molecular Neurobiology, vol. 15, 527-545). In normal rat adenohypophysis where GnRH receptors reside, GnRH leads to an increased cAMP production, however, it is still unclear whether this is a direct or an indirect effect (paracrine interaction). For the function of the GnRH receptor in rat including secretion of LH as well as an increased production of LH stimulated by GnRH, the biochemical metabolization of GnRH, e.g. by means of cAMP, plays only an indirect role (Abdilnour, G., and Bourne, G. A., 1995, Adenosine 3′,5′-cyclic mono-phosphate and the self-priming effect of gonadotropin-releasing hormone. Molecular and Cellular Endocrinology, 107, 1-7). Naturally, there were found GnRH receptors on human gonadotropin producing pituitary adenomas (Alexander, J. P., and Klibanski, A., Gonadotropin-releasing Hormone Receptor mRNA Expression by Human Pituitary Tumors In Vitro, 1994, Journal of Clinical Investigation, 93, 2332-2339).
In the case of glioma and other malignant tumors of ectodermal origin, such as malignant melanoma and in particular in the case of diffusely growing tumors in the nervous system or in the case of metastases (formation of disseminations, for example, in other organs such as oat-cell carcinoma in the lung) life expectancy is not optimistic. The same is true for Kaposi sarcoma. “Glioma” refers to mainly brain-localized true tumors of the central nervous system (CNS) originating in the neuroglia, i.e. from the covering and supporting tissue of the nervous system which is derived from ectoderm. These gliomas are present in various differentiation stages. Subtypes of glioma are spongioblastoma, oligodendroglioma, astrocytoma, glioblastoma, and retinoblastoma. In particular, the Glioblastoma multiforme (GBM) type of brain tumors is characterized by fast growth and extremely high recidivation rate (i.e., the percentage of patients with brain tumor recurrence following surgical macroscopic excision).
Malignant melanoma occurring in the CNS, primary or as metastasis, as well as malignant melanoma which primarily occurs in the skin and/or malignant melanoma which disseminates (metastasizes) further in the skin and/or in other body organs belong to nerve system derived tumors; cf. Shamamian et al., 1994, Cancer Immunol. Immunother. 39, 73-83; Florenes et al., 1994, Cancer Research, 54, 354-356. Malignant melanomas are derived from neuroectoderm, an embryonic layer. Burg et al., 1997, Deutsches Ärzteblatt 94, 890-895, describe a tumor growth inhibiting effect of tamoxifen for the malignant melanoma. Furthermore, glioblastoma and malignant melanoma have several tumor markers in common; cf. Shamamian et al., 1994, Cancer Immunol. Immunother. 39, 73-83; Florenes et al., 1994, Cancer Research 54, 354-356. In the case of metastases, the prognosis is very poor; cf. Burg et al., 1997, Deutsches Arzteblatt 94, 890-895.
Tumors originating in brain and/or nervous system and/or the meninges further comprise the neuroblastoma and the medullablastoma which in their entirety have been classified as the so-called primitive neuroectodermal tumors, abbreviated as PNET. These tumors further include the pinealoma originating in pineal body parenchyma and/or primordial germ cells in the pineal body region or the brain median. Moreover, the pineal body is associated with the origin of craniopharyngeoma (a tumor producing β-HCG or LH-like glycoprotein, respectively; cf. Tachibana et al., 1994, J. of Neurosurgery 80, 79-84) which is considered to be an ectodermal tumor and originates in the front/upper face of the pituitary.
Both for craniopharyngeoma and meningeoma which is considered to be a benign tumor originating in arachnoidal cover cells and often adhering firmly to the inner surface of the meninges (dura mater), progesterone receptors and estrogen receptors have been described. Furthermore, androgen receptors have also been established in the case of meningeoma. In clinical studies using anti-progesterone medicaments, tumor-shrinking effects have been observed.
Up to now, the investigation of other therapies (different forms of chemotherapy, radiotherapy, etc.) in numerous clinical studies has failed to provide a substantial improvernent of the prognosis for tumors originating in brain and/or nervous system and/or the meninges. At present, the standard therapy in the case of Glioblastoma multiforme consists of an as complete as possible surgical excision of the tumor followed by conventional radiotherapy. Under this standard therapy the statistically reported mean survival time is 9-13 months with individual variations and particularly a slightly better prognosis for younger patients having been observed.
About 30% of patients with recurrent Glioblastoma multiforme showed constant size or shrinking, respectively, of the inoperable residual brain tumor under sustained high-dosage of Tamoxifen, an anti-estrogen preparation. This tumor-inhibiting effect in glioblastoma treatment has not been attributed to its anti-estrogenic effect but to its inhibition of protein kinase C (an intracellular signal mediator); cf. Puchner et al., Zentralblatt für Neurochirurgie, Supplement 1996, 47. Jahrestagung Deutsche Gesellschaft für Neurochirurgie, page 44; Pollack et al., 1995, The Efficacy of Tamoxifen as an anti-proliferative Agent in vitro for Benign and Malignant Pediatric Glial Tumors, Pediatr. Neurosurgery 22, 281-288). Moreover, Tamoxifen is said to increase the sensitivity of tumor cells for platinium-containing therapeutics as well as for radiotherapy.
For Glioblastoma multiforme (WHO grade IV astrocytoma) and for glioma with a lower grade of malignancy (WHO grade II-IV astrocytoma) steriod hormone receptors have been observed in a smaller percentage of the cases (cf. Paoletti et al., 1990, J. Neurosurgery, Characteristics and biological role of steroid hormone receptors in neuroepithelial tumors, 73, 736-742). Up to now, an indirect anti-proliferative effect in the case of Glioblastoma multiforme and glioma grade II-IV has been observed in clinical studies in only about 30% of the cases by a response of the tumor to Tamoxifen (an anti-estrogen preparation).
Although recently, several relatively reasonable new developments in Glioblastoma multiforme therapy have been described, the prognosis quod vitam for patients with Glioblastoma multiforme remains poor due to the extremely high recurrence rate despite the therapy forms tried and tested so far and due to the lack of a specific therapy and early diagnosis. The oat-cell carcinoma, another malignant tumor, is frequently found in lungs and is also derived from neural cells (Tecimer et al Arch. Pathol. Lab. Med., 124, 520-525, 2000).